Process for treating helminth infestations using benzanilide derivatives and compositions for use therein



United States Patent US. Cl. 424233 11 Claims ABSTRACT OF THE DISCLOSURECompositions and process for treating helminth infestations in animalswherein the active coponent is a benzanilide derivative such as3,35,5',6-pentachloro-2,2-dihydroxybenzanilide.

This invention relates to new pharmaceutical compositions and moreparticularly it relates to new pharmaceutical compositions which containas the active ingredients benzanilide derivatives which are of value inthe treatment of animals suffering from helminth infestations.

According to the invention we provide new pharmaceutical compositionscharacterised by the presence therein as active ingredient(s) of one ormore benzanilide derivatives of the formula:

W (1)11 HO M X- 4 3 2} -CO.NH% g P l l l Y Z R Q,

wherein W, X, Y, Z, M, P, Q and R, which may be the same or different,stand for hydrogen, chlorine or bromine provided that not more than twoof W, X, Y and Z, and not more than two of M, P, Q and R, stand forhydrogen, or the pharmaceutically-acceptable salts thereof together witha pharmaceutically-acceptable diluent or carrier therefore.

Suitable benzanilide derivatives of the above stated formula are, forexample 3,3',5,5',6'pentachloro-2,2-dihydroxybenzanilide, 3,3',5 ,5',6-pentachloro-2,2'-dihydroxybenzanilide,3,3,5,5',6,6'-hexachloro-2,2-dihydroxybenzanilide, 3,3',4,5 ,5,6,6-heptachloro-2,2-dihydroxybenzanilide, 3,3 '5 ,5'tetrachloro-2,2-dihydroxybenzanilide and 3,3',4',5 ,5',6'-hexachloro-2,2'-dihydroxybenzanilide.

Suitable pharmaceutically-acceptable salts of the benzanilidederivatives used as active ingredients in the compositions of thepresent invention .are, for example, alkali metal and alkaline earthmetal salts, for example the sodium and calcium salts, and the salts ofnon-toxic organic bases, for example piperazine salts.

The pharmaceutical compositions of the invention may be designed eitherfor oral or for parenteral administration and may be, for example, inthe form of tablets, boluses, capsules, aqueous or oily solutions,aqueous or oily suspensions, emulsions, sterile injectable aqueous oroily solutions or suspensions, dispersible powders, premixes suitablefor addition to animal foodstuffs or mixtures with animal foodstuffs.

The compositions of the invention may contain standard excipients knownto the art to be useful in the formulation of such compositions and theymay contain, for example, inert diluents, fillers, disintegratingagents, bac- 3,466,370 Patented Sept. 9, 1969 "ice teriostats,bactericidal agents, sporicidal .agents, stabilising agents, thickeningagents, preservatives, wetting agents, dispersing agents, suspendingagents and pharmaceuticallyacceptable colouring agents. The compositionsmay also optionally contain other substances of veterinary utility, forexample vitaminaceous materials, drugs of veterinary utility and mineralsalts.

Suitable tablets and boluses may be formulated by admixture of theactivet ingredient(s) with known pharmaceutical excipients, for exampleinert diluents, for example calcium carbonate, calcium phosphate orlactose, disintegrating agents, for example maize starch or alginicacid, binding agents, for example starch, gelatin or acacia mucilage,lubricating agents, for example magnesium stearate, stearic acid ortalc, and wetting agents, for example the alkali metal salts ofsulphonated dialkylnaphthalenes. Such tablets may optionally be coatedby known techniques in order to delay disintegration in the uppergastrointestinal tract.

Compositions in the form of capsules may consist, for example, ofgelatine capsules containing active ingredient(s) only or the activeingredient(s) in admixture with inert diluents, for example lactose orsorbitol, or, for example, in solution or suspension in a vegetable oil.

The aqueous suspensions, emulsions, oily solutions and suspensions ofthe invention may contain a sweetening agent, for example glycerol,dextrose or sucrose, and a fiavouring agent, for example vanillin ororange extract, in order to provide a palatable product. The aqueoussuspensions of the invention may also contain suitable suspending orthickening agents, for example sodium carboxymethylcellulose, wettingagents, for example condensation products of fatty alcohols withethylene oxide, and suitable preservatives, for example methyl or propylphydroxybenzoate.

The emulsion compositions of the invention may contain the activeingredient(s) dissolved in a suitable fat of vegetable or animal origin,for example arachis oil or cod liver oil, and may also containsweetening agents and flavouring agents which may with advantage beessential oils. The emulsions may also contain emulsifying agents anddispersing agents, for example soya bean lecithin, polyoxyethylenesorbitan mono-oleate, gum acacia, gum tragacanth or casein, andpreservatives, for example methyl or propyl p-hydroxybenzoate, andanti-oxidants, for example propyl gallate.

The oily solutions of the invention likewise may contain the activeingredient(s) in solution in a suitable fat of vegetable or animalorigin, and may optionally contain flavouring agents to mask the tasteand improve oral acceptability. The oily solutions may also containsweetening agents, for example icing sugar, in which case the oil phasemay in addition contain a suspending agent, for example beeswax, tomaintain the redispersion properties of the suspension.

The sterile injectable aqueous suspensions of the invention may containa suspending or thickening agent, for example sodiumcarboxymethylcellulose, and a wetting or dispersing agent, for example aphenolpolyethylene oxide condensate, for example the condensationprodnot of octylcresol with about 8-l0 moleucular proportions ofethylene oxide. The injectable oily solutions of the invention may beprepared from a non-toxic injectable fat or oil, for example arachis oilor ethyl oleate, and they may additionally contain gelling agents, for,example aluminum stearate, to delay adsorption within the body. Theseaqueous and oily injectable preparations may contain preservatives suchas methyl or npropyl p-hydroxybenzoate or chlorobutenol.

The dispersable powders of the invention may contain the activeingredient(s) in admixture with suitable wetting, dispersing andsuspending agents.

The premixes of the invention preferably contain between 1% and 25% byweight of the active ingredient(s) and may contain the active ingredientin admixture with non-toxic diluents or carriers, for example talc,kaolin, chalk, lactose, urea, corn or meal, ground oyster shells,distillers dried grains and edible vegetable substances, for examplecommercial animal foodstuffs.

The mixtures with animal foodstuffs which are intended to be orallyadministered as such to domestic animals preferably contain between0.01% and 2% by weight of the benzanilide derivative(s) used as activeingredient( s) As stated above the pharmaceutical compositions of theinvention may optionally additionally contain other substances ofveterinary utility, for example drugs of veterinary utility. Suitabledrugs of veterinary utility are, for example, anthelmintic drugs, forexample, phenothiazine or methyridine and antibacterial drugs, forexample benzylpenicillin, or sulphaguanidine.

The benzanilide derivatives used as active ingredients in thecompositions of the present invention may be prepared by conventionalmethods, for example, by interaction of a reactive derivative of anappropriately substituted salicylic acid, for example the correspondingcarboxylic chloride, and a suitably substituted o-aminophenol.

The compositions of the invention are effective in the treatment ofhelminth infestations, for example they are effective in removing liverfluke from domestic animals.

Accordingly, therefore, we provide a process for the treatment ofhelminth infestations in animals which comprises the administrationthereto of an effective amount of one or more benzanilide derivatives ofthe formula:

OH HO wherein W, X, Y, Z, M, P, Q and R which may be the same ordifferent, stand for hydrogen, chlorine or bromine provided that notmore than two of W, X, Y and Z, and not more than two of M, P, Q and R,stand for hydrogen, or the pharmaceutically-acceptable salts there. of.

The process for the treatment of domestic animals, particularly sheepand cattle, by administration of the pharmaceutical compositions of theinvention will depend upon the weight of the animal to be treated, theseverity of the helminth infestations of the animal concerned and itsgeneral condition of health at the time of treatment. Administration ofone or more doses at the rate of 5100 mg. of active ingredient per kg.of body weight of animals and more particularly at a dosage rate ofabout 550 mg. of active ingredient per kg. of body weight of animal issatisfactory for the treatment of helminth infestations.

The invention is illustrated but not limited by the following examplesin which the parts are by weight.

Example 1 parts of 3,3',5,5,6-pentachloro-2,2-dihydroxybenzanilide, M.P.224 C., are ball-milled with 90 parts of a solution obtained bydissolving in 1,000 parts of water 1 part of a condensate of 1 molecularproportion of octylcresol with about 9 molecular proportions of ethyleneoxide and 1 part of polyglycerolricinoleate. There is thus obtained anaqueous suspension suitable for oral administration to domestic animalsfor the control of helminth infestations, for example liver flukeinfestations.

Example 2 10 parts of 3,3',5,5,6,6-hexachloro-2,2'-dihydroxybenzanilide,M.P. 226 C., are ball-milled with 90 parts of a solution obtained bydissolving in 1,000 parts of water 2.5 parts of a condensate of 1molecular propor- 4 tion of octycresol with about 9 molecularproportions of ethylene oxide. There is thus obtained a suspensionsuitable for administration to domestic animals for the treatment ofhelminth infestations, for example liver fluke infestations.

Example 3 100 parts of 3,3',5,5,6-pentachloro-2,2-dihydroxybenzanilideare mixed with 1 part of sodium ligninsulphonate and 2 parts of thesodium salt of a butylated-naphthalene sulphonic acid. The mixture thusobtained is reduced in particle size by passage through a mill. There isthus obtained a dispersible powder which can be added to water to forman aqueous suspension suitable for administration to domestic animalsfor the treatment of helminth infestations, for example liver flukeinfestations.

Example 4 A mixture of 5 parts of 3,3',5,5',6,6'-hexachloro-2,2'-dihydroxybenzanilide and parts of maize oil is stirred at 50 C. for 30minutes and is then. allowed to cool. There is thus obtained an oilysolution suitable for administration to domestic animals for thetreatment of helminth infestations, for example liver flukeinfestations.

Example 5 A mixture of parts of 3,3',4',5,5',6,6'-heptachloro-2,2-dihydroxybenzanilide, M.P. 243 C., and 400 parts of calciumphosphate is passed through a 60-mesb sieve. To the mixture are thenadded 30 parts of starch in the form of an aqueous paste and theresultant mxiture is blended and compressed into granules. The granulesare passed through a lO-mesh sieve and dried at 50 C. The dried granulesare passed through a 2O-mesl1 sieve and are then blended with a mixtureof 5 parts of gum acacia and 20 parts of starch. To the mixture thusobtained there is added 10 parts of talc and 1 part of magnesiumstearate and the resulting mixture is blended and then compressed intoboluses which are suitable for administration to domestic animals forthe treatment of helminth infestations, for example liver flukeinfestations.

Example 6 A mixture of 100 parts of 3,3,5,5',6'pentachloro-2,2-dihydroxybenzanilide, 10 parts of maize starch, 10 parts of lactose and2 parts of magnesium stearate is compressed into slugs and the slugs arepassed through an S-mesh sieve and then through a 16-mesh sieve. Thegranules thus obtained are then compressed into tablets which aresuitable for administration to domestic animals for the treatment ofhelminth infestations, for example liver fluke infestations.

Example 7 2 parts of the piperazine salt of 3,3',5,5,6,6-hexachloro-2,2'-dihyd.roxybenzanilide are intimately mixed with 80 parts ofdistillers dried grains. There is thus obtained a premix suitable foraddition to animal foodstuffs for the treatment of helminthinfestations, for example liver fluke infestations, in domestic animals.

Example 8 20 parts of 3,3-5,5'-tetrachloro-2,2'-dihydroxybenzanilide areintimately mixed with 80 parts of wheat standard middling. There is thusobtained a premix suitable for addition to animal foodstuffs for thetreatment of heminth infestations, for example liver fluke infestations,in domestic animals.

Example 9 100 parts of the calcium salt of 3,3',5,5',6,6-hexachloro-2,2-dihydroxybenzanilide are mixed with 1 part of sodiumligninsulphonate and 1 part of the sodium salt of abu-tylated-naphthalene-sulphonic acid. The mixture thus obtained isreduced in particle size by passage through a mill and there is thusobtained a dispersible powder which can be added to water to form anaqueous suspension suitable for administration to domestic animals forthe treatment of helminth infestations, for example liver flukeinfestations.

Example Three ewes, each with a liver fluke infestation, were treated byoral administration of 3,3',5,5',6,6-hexachloro 2,2-dihydroxybenzanilideas a suspension prepared as described in Example 2. The amount of drugadministered was at the rate of 25 mg./kg. of body weight. During thesix days following treatment the ewes expelled a total for each ewerespectively of 5, 34 and 86 dead adult lever fluke. The ewes were thenkilled. At post mortem no fluke were found in the livers of two of theanimals while in the liver of the third ewe seventeen immature fluke butno adult fluke were found.

Example 11 25 parts of the piperazine salt of 3,3',5,5,6-pentachloro-2,2-dihydroxybenzanilide are intimately mixed with 75 parts ofdistillers dried grains. There is thus obtained a premix suitable foraddition to animal foodstuffs for the treatment of helminthinfestations, for example liver fluke infestations.

Example 12 A- mixture of 150 parts of the calcium salt of 3,3',5,5,6-pentachloro-2,2-dihydroxybenzanilide and 350 parts of calcium phosphateis passed through a 60-mesh sieve. To the mixture are then added 25parts of starch in the form of an aqueous paste and the resultantmixture is blended and compressed into granules. The granules are passedthrough a IO-mesh sieve and dried at 50 C. The dried granules arefurther passed through a ZO-mesh sieve and are mixed with a mixture of 5parts of gum acacia and 20 parts of starch. To the mixture thus obtainedthere are added 18 parts of talc and 1 part of magnesium stearate andthe resulting mixture is blended and then compressed into tablets whichare suitable for administration to domestic animals for the treatment ofhelminth infestation, for example liver fluke infestations.

Example 13 10 parts of 3,3',5,5',6-pentachloro-2,2'-dihydroxybenzanilideare dissolved in a solution of 2 parts of sodium hydroxide in 50 partsof water. Dilute hydrochloric acid is then added to the solution untilthe pH of the solution is 10 and the solution is thereafter filteredthrough a Seitz filter and the filtrate is filled into ampoules. Thereis thus obtained a sterile solution suitable for parenteraladministration to animals for the treatment of helminth infestations.

Example 14 Two ewes, each with a liver fluke infestation, were treatedby oral administration of 3,3',5,5',6-pentachloro-2,2'-dihydroxybenzanilide as a suspension prepared as described inExample 1. The drug was administered at the rate of 10 mg./ kg. of bodyweight in the case of the first ewe and 15 mg./kg. of body weight in thecase of the second ewe. During the six days following treatment thefirst ewe expelled a total of 94 fluke and the second ewe expelled atotal of 100 fluke. The ewes were then killed. At post mortem no flukewere found in the livers of either ewe.

Example 15 Three cows, each with a liver fluke infestation, were treatedby oral administration of 3,3',5,5',6-pentachloro-2,2-dihydroxybenzanilide as a suspension prepared as described inExample 1. The amount of drug administered was at the rate of 10 mg./kg.of body weight. During the three days following treatment the cowsexpelled a total for each cow respectively of 94, 100 and 88 flukes Thecows were killed six days following treatment. No flukes were found inthe livers of the animals on post mortem examination.

What we claim is:

1. A composition for the treatment of helminth infestations comprisingas active ingredient, an anthelmintically effective amount of at leastone compound selected from the group consisting of benzanilidederivatives of the formula:

I I Y Z wherein W, X, Y, Z, M, P, Q and R are selected from the groupconsisting of hydrogen, chlorine and bromine provided that at least twoof W, X, Y and Z are selected from the group consisting of chlorine andbromine and that at least two of M, P, Q and R are selected from thegroup consisting of chlorine and bromine, and the alkali metal, alkalineearth metal and nontoxic pharmaceutically-acceptable organic base saltsthereof, together with a pharmaceutically-acceptable carrier therefor.

2. A composition as claimed in claim 1, wherein the benzanilidederivatives are selected from the group consisting of3,3',5,5,6'-pentachloro-2,2-dihydroxybenzanilide,3,3,5,5',6-pentachloro-2,2-dihydroxybenzanilide, 3, 3,5,5,6,6 hexachloro2,2'-dihydr0xybenzanilide, 3,3, 4,5,5',6,6heptachloro-Z,2-dihydroxybenzanilide, 3,3,5, 5-tetrachloro2,2-dihydroxybenzanlide and 3,3,4',5,5',6-hexachloro-2,2'-dihydroxybenzanilide.

3. A composition, as claimed in claim 1, which additionally containsanother drug of veterinary utility selected from the group consisting ofphenothiazine, methyridine, benzylpenicillin and sulphaguanidine.

4. A- composition as claimed in claim 1 wherein the salts are selectedfrom the group consisting of sodium, calcium and piperazine salts.

5. A composition as claimed in claim 1 which is in a form selected fromthe group consisting of tablets, boluses, capsules, aqueous and oilysolutions, dispersible powders, and mixtures with animal feeds.

6. A composition as claimed in claim 1 which contains between 1% and 25%by weight of the active ingredient.

7. A composition as claimed in claim 5, wherein the active ingredient isin admixture with at least one member of the group consisting of talc,kaolin, chalk, lactose, urea, corn or meal, ground oyster shells,distiller dried grains and edible vegetable substances.

8. A composition as claimed in claim 5, which is a mixture with ananimal feed and contains between 0.01% and 2% by weight of activeingredient.

9. A composition as claimed in claim 5 which is an aqueous suspensionand which contains as active ingredient 3,3,5,5.6 pentachloro 2,2dihydroxybenzanilide together with a wetting agent which is acondensation produce of a fatty alcohol with ethylene oxide.

10. Process for the treatment of helminth infestations in animals whichcomprises the administration thereto of an anthelmintically-effectiveamount of at least one compound selected from the group consisting ofbenzanilide derivatives of the formula:

W $11 H(I) l\1 I I I I Y z P Q,

wherein W, X, Y, Z, M, P, Q and R are selected from the group consistingof hydrogen, chlorine and'bromine provided that at least two of W, X, Yand Z are selected 3,466,370 7 8 from the group consisting of chlorineand bromine and References Cited at least two of M, P, Q and R areselected from the group UNITED STATES PATENTS consisting of chlorine andbromine, and the alkali metal,

alkaline earth, and nontoxic pharmaceutically-acceptable 3 52? 260454organic base salts thereof, the amount of antheliminti- 5 3072573 1/1963Spacht cally-effective compound being in the range of 5 to 100 mg. perkg. of body weight of the animal treated. FRANK CACCIAPAGLIA, JR.,Primary Examiner 11. A process as claimed in claim 10 wherein there isadministered an anthelminticallyeffective amount of 3,3,

5,5,6-pentachlor0-2,2'-dihydroxybenzanilide. 424247, 263, 271, 324

